Acute lung injury, such as that seen with adult and pediatric respiratory distress syndromes, is characterized by endothelial injury, and pulmonary edema. High concentrations of oxygen (hyperoxia; 100% O2) are commonly administered to patients in these clinical scenarios. Although such concentrations of O2 are considered therapeutic since they increase alveolar and arterial oxygen tension and augment tissue O2 delivery, they also contribute to the generation of acute lung injury and the perpetuation and/or worsening of respiratory distress syndromes. Surprisingly, little is known about the mechanisms by which hyperoxia injures blood vessels and induces pulmonary edema. We undertook studies designed to determine if VEGF, Angiopoietin 1 or Angiopoietin 2 are regulated by hyperoxia-induced acute lung injury. Our studies demonstrated a marked induction of Angiopoietin 2, a modest induction of VEGF, and a marked decrease in Angiopoietin 1 during the course of this insult. These changes were reversed when the mice were allowed to recover from hyperoxia-induced acute lung injury. We also demonstrated that transgenic VEGF induces pulmonary edema when overexpressed in a lung-specific fashion and that hyperoxiainduced acute lung injury is ameliorated in Angiopoietin 2 null mutant animals. As a result of these findings, we have generated the following hypotheses: 1. Endothelial injury and permeability changes in the setting of hyperoxia-induced acute lung injury are mediated via alterations in VEGF, Angiopoietin 1, and Angiopoietin 2. 2. The permeability alterations seen in respiratory distress syndromes are mediated, in part, by the increase in VEGF, increase in Angiopoietin 2, and decrease in Angiopoietin 1 that is seen in this setting. Specific Aims: Characterize the alterations in VEGF, Angiopoietin 1 and Angiopoiefin 2 in a model of hyperoxia-induced acute lung injury in adult mice. Define the contributions that VEGF, Angiopoietin 1, and Angiopoiefin 2 make to the pathogenesis ofhyperoxiainduced acute lung injury in adult mice. Determine the differences and the degree to which the response to hyperoxia-induced acute lung injury differs in adult, newborn and fetal mice with regard to VEGF, Angiopoietin 1 and Angiopoietin 2.